A B S T R A C T Abrupt withdrawal after the chronic administration of propranolol has resulted in clinical syndromes that suggest adrenergic hypersensitivity. The effect of propranolol administration and withdrawal on ,-adrenergic receptors was studied in human lymphocyte membranes. Receptor density was quantitated by direct binding assays with the radioligand [1251]iodohydroxybenzylpindolol. Administration ofpropranolol (160 mg/d) for 8 d resulted in trough plasma levels of -35 ng/ml. By day 5 ofpropranolol administration the density of /3-adrenergic receptors had increased 43+4% (P < 0.01) above pretreatment levels. Abrupt withdrawal of propranolol was followed by the disappearance of propranolol from the plasma within 24 h. The density of f3-adrenergic receptors did not return to pretreatment level for several days. Physiologic supersensitivity of 8-adrenergic receptor-mediated responses was suggested by the appearance of significant increases in the orthostatic change in heart rate (P < 0.05) and the orthostatic change in the heart rate-systolic blood pressure product (P < 0.01) during the first 48 h after propranolol withdrawal. These data show that propranolol administration leads to an increase in the density of f3-adrenergic receptors in human tissue. The results are consistent with the hypothesis that some of the untoward effects observed after abrupt discontinuation of propranolol are caused by 8-receptor-mediated adrenergic hypersensitivity.

Exposure to chronic hypoxia results in a lower resting heart rate and a blunted cardiovascular responsiveness to beta-adrenergic receptor stimulation. Possible effects of acclimatization to high altitude on the binding of [125I]iodohydroxybenzylpindolol to beta-adrenergic receptors on membranes of right and left ventricles of rat heart were determined. Chronic high-altitude exposure led to a decrease in the density of beta-adrenergic receptors in nonhypertrophied left ventricles as well as in hypertrophied right ventricles. The affinity of the receptor for the radioligand was not changed by the exposure to high altitude, suggesting that the properties of the receptor were not affected. Basal and isoproterenol-stimulated adenylate cyclase activities were decreased in membranes prepared from hearts and pulmonary arteries of rats acclimatized to high altitude. The loss of cardiac beta-adrenergic receptors in rats adapted to high altitude was prevented by the chronic coadministration of a low dose of DL-propranolol. The results suggest that changes in beta-adrenergic receptor density may partially explain the hemodynamic adaptation that occurs with chronic hypoxia. These decreases may be due to a loss of functional beta-adrenergic receptors caused by chronically elevated concentrations of circulating neurally released catecholamines.

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